HIV-infected injection drug users (IDUs) represent a marginalized population with substantial disparities in health care access and outcomes. With improved survival due to highly active antiretroviral therapy (HAART), HIV has transformed into a chronic disease. In addition to HIV disease, IDUs also suffer from a syndemic of other chronic diseases including substance abuse, mental health disorders, and non-AIDS comorbidities. Proposed is a continuation of the ALIVE cohort study, among the largest, longest-running and productive IDU cohorts worldwide, and which has followed disadvantaged, primarily African American IDUs in Baltimore, MD since 1988. With advancing age and multimorbidity, the comprehensiveness of care will increasingly determine HIV-infected IDUs quality and quantity of life. We hypothesize that the key determinants of optimal HIV care (e.g., active drug use, provider relationships, social networks, neighborhood factors) may also determine effective comprehensive care for HIV-infected IDUs. While this cohort has and continues to be a platform for an array of studies all critical to addressing questions about the long-term course and consequences of HIV disease and its treatment among IDUs, this proposal emphasizes: 1) improved identification of HIV-infected IDUs most likely to respond optimally to ART. We will examine longitudinal trajectories of drug use and HIV RNA to define membership in optimal vs. sub-optimal response groups, and then quantitatively identify behavioral and clinical correlates and qualitatively examine barriers and coping mechanisms which underlie the ability to optimally respond. 2) To investigate the determinants and consequences of comprehensive care for HIV-infected IDUs from patient, clinical and societal perspectives. Comprehensive care for HIV-infected IDUs extends beyond HIV-focused aspects to include care for chronic comorbid diseases, substance abuse, and mental health conditions. We propose a framework that considers measures of effective comprehensive care from patient (perceived effectiveness), clinical (adherence to quality care indicators) and societal (service utilization) points of view. Building on prior investigation of individual-, provider-, and neighborhood-level factors associated with HAART effectiveness, we will identify determinants of quality comprehensive care. Extending our multi-level framework in this proposal, we will also evaluate the role of social networks (e.g. 'care-engaged' network members) on comprehensive care. Finally, we examine comprehensive care effectiveness in relation to patient-reported (quality-of-life), clinica (multimorbidity, physical performance) and societal (QALYs) outcomes. To achieve these aims, we continue biannual visits with interview, exam, and biospecimen collection supplemented by medical record review and registry linkage. The ALIVE study remains well-positioned to address the emerging issues confronting the healthy aging of HIV-infected IDUs, namely optimizing long-term ART and enhancing comprehensiveness of care. PUBLIC HEALTH RELEVANCE: This proposal addresses the primary issues confronting the healthy aging of HIV-infected injection drug users, namely optimizing long-term antiretroviral therapy and enhancing the comprehensiveness of care, not just for HIV disease, but also for substance abuse, mental health conditions, and chronic diseases. Nested in the long- standing ALIVE cohort study, the proposed aims will improve understanding of effective comprehensive care from patient, clinical and societal perspectives, and will inform strategies to optimize care and improve outcomes for persons aging with HIV infection.